One of the many common complications of diabetes is angiopathy, or abnormality of the blood vessels. Angiopathy of this sort is thought to be mediated by the action of the enzyme aldose reductase. The condition generally results in abnormalities categorized by reduced blood flow, weakening of vessel walls with the tendency to develop aneurysms, restenosis, atherosclerosis, and other conditions. Diabetic angiopathy results in a chronic degradation of vessel structure, to the point where the condition becomes severely life-threatening.
Current methods do little to reduce or obviate the onset of diabetic angiopathy. The current popular treatment involves the administration of angiotensin converting enzyme (ACE) inhibitors such as captopril, to patients with chronic angiopathy as a result of diabetes. Calcium channel blockers have also been administered for this purpose, and a high protein diet has also been suggested to slow the onset of angiopathy. It has been suggested that the only true way to prevent diabetic angiopathy (and other diabetic complications) is through strict glycemic control.
Aldose reductase (AR) inhibitors have been tested in humans, mainly in the 1980s, with the hope that these agents would slow the progress of diabetic retinopathy, a condition that often led to blindness. The AR inhibitors (sorbinil was one of those tested) showed some efficacy, but were not well tolerated by patients. No AR inhibitor to date has been approved for use in the United States for diabetic angiopathy or any other indication.
Mesna (sodium 2-mercaptoethene sulfonate) and dimesna (disodium 2,2'-dithiobis ethane sulfonate) are known therapeutic compounds, which have heretofore demonstrated a wide variety of therapeutic uses. Both mesna and dimesna have been shown to be effective protective agents against certain specific types of toxicity associated with the administration of cytotoxic drugs used to treat patients for various types of cancer. In particular, mesna has been used with some success in mitigating the toxic effects of cytotoxic agents such as ifosfamide, oxazaphosphorine, melphalane, cyclophosphamide, trofosfamide, sulfosfamide, chlorambucil, busulfan, triethylene thiophosphamide, triaziquone, and others, as disclosed in U.S. Pat. No. 4,220,660, issued Sep. 2, 1980.
The near absence of toxicity of dimesna further underscores the usefulness of this compound, as large doses that can be given to a patient without increasing the risk of adverse effects from the protective agent itself.
Further, pharmacological profiles of each compound indicate that, if proper conditions are maintained, mesna and dimesna do not prematurely inactivate primary therapeutic drugs to a significant degree. Thus, neither compound will significantly reduce activity of the chemotherapeutic agent, and in many cases, act to potentiate the effect of the main drug on targeted cancer cells.
The structures of both mesna and dimesna are shown below as Formula a and Formula b respectively. EQU SH--CH.sub.2 --CH.sub.2 --SO.sub.3 Na (a) EQU NaO.sub.3 S--CH.sub.2 --CH.sub.2 --S--S--CH.sub.2 --CH.sub.2 --SO.sub.3 Na (b)
As is well known, dimesna is a dimer of mesna, with the optimum conditions for oxidation occurring in the slightly basic (pH .about.7.3), oxygen rich environment found in blood plasma. In mildly acidic, low oxygen conditions, in the presence of a reducing agent such as glutathione reductase, conditions prevalent in the kidneys, intracellular spaces, intestines, and others, the primary constituent is mesna.
Mesna acts as a protective agent for a number of cytotoxic agents by substituting a nontoxic sulfhydryl moiety for a toxic hydroxy (or aquo) moiety. This action is particularly evidenced in the coadministration of mesna and oxazaphosphorine, and in the administration of dimesna along with cisplatin, carboplatin, and taxane derivatives.
Mesna and dimesna, as well as some analogues of these compounds, have excellent toxicity profiles in mammalian species. In fact, dimesna has been administered intravenously to mice and dogs in doses higher than the accepted oral LD.sub.50 for common table salt (3750 mg/kg), with no adverse effects. Dimesna has also been administered to humans in doses exceeding 15 g/m.sup.2, with no adverse effects.
Mesna, and other analogues with free thiol moieties, constitute the more physiologically active form of the two types of compounds described in this specification. These compounds manifest their activity by providing free thiol moieties for terminal substitution at locations where a terminal leaving group of appropriate configuration is located.
Dimesna and other disulfides can be activated intracellularly by glutathione reductase, a ubiquitous enzyme, thereby generating high concentrations of intracellular free thiols. These free thiols act to scavenge the free radicals and other nucleophilic compounds often responsible for causing cell damage.
This profile is especially significant in explaining the success of dimesna in controlling and mitigating the toxic effects of platinum complex antitumor drugs. The mechanism for action in the case of cisplatin (cis-diammine dichloro platinum) is explained in U.S. Pat. No. 5,789,000, which is incorporated herein by reference.
Mesna, dimesna, and analogues of these compounds have been the subject of several prior pharmaceutical uses described in the literature and in prior patents, both in the United States and around the world. In addition to the cytotoxic agent protection uses, one or more of these compounds have proven effective, in vitro, against a multiplicity of biological targets, and have been effective, in vivo, in the treatment of sickle cell disease, radiation exposure, chemical agent exposure, and other uses.
Mesna, dimesna, and analogues thereof are synthesized from commonly available starting materials, using acceptable routes well known in the art. One such method involves the two-step, single pot synthetic process for making dimesna and like compounds of the following formula:
R.sub.1 --S--R.sub.2 ;
wherein:
R.sub.1 is hydrogen, X-lower alkyl, or X-lower alkyl-R.sub.3 ; PA1 R.sub.2 is -lower alkyl-R.sub.4 ; PA1 R.sub.3 and R.sub.4 are each individually SO.sub.3 M or PO.sub.3 M.sub.2 ; PA1 X is absent or X is sulfur; and PA1 M is an alkali metal. PA1 R.sub.1 is hydrogen, lower alkyl or ##STR2## PA1 R.sub.2 and R.sub.4 are each individually SO.sub.3.sup.- M.sup.+, PO.sub.3.sup.2- M.sub.2.sup.2+, or PO.sub.2 S.sup.2- M.sub.2.sup.2+ ; PA1 R.sub.3 and R.sub.5 are each individually hydrogen, hydroxy or sulfhydryl; PA1 m and n are individually 0, 1, 2, 3 or 4, with the proviso that if m or n is 0, then R.sub.3 is hydrogen; and PA1 M is hydrogen or an alkali metal ion; or
The process essentially involves a two step single pot synthetic process, which results in the conversion of an alkenyl sulfonate salt or acid to the desired formula I compound. The process in the case of mesna is a single step process, which converts the alkenyl sulfonate salt to mesna or a mesna derivative by reacting with an alkali metal sulfide or with hydrogen sulfide.
If the desired end product is dimesna or a dimesna analogue, a two-step single pot process is involved. Step 1 is as described above. Step 2 of the process is performed in the same reaction vessel as Step 1 without the need to purify or isolate the mesna formed during that step. Step 2 includes the introduction of oxygen gas into the vessel, along with an increase in pressure and temperature above ambient values, at least 20 pounds per square inch (psi) and at least 60.degree. C. Dimesna or a derivative thereof is formed in essentially quantitative yield.
Other processes, well known and documented in the prior art, may be employed to make either mesna or dimesna, or derivatives and analogues thereof.